Synthetic Immunotherapeutics against Gram-negative Pathogens. Issue 10 (18th October 2018)

• Record Type: Journal Article
• Authors: Feigman, Mary Sabulski; Kim, Seonghoon; Pidgeon, Sean E.; Yu, Yuming; Ongwae, George Mogambi; Patel, Dhilon S.; Regen, Steven; Im, Wonpil; Pires, Marcos M.
• Is Part Of: Cell chemical biology. Volume 25:Issue 10(2018)
• Page Start: 1185
• Page End: 1194.e5
• Publication Date: 2018-10-18
• Subjects: antimicrobials -- bacterial cell surface -- immunotherapy -- antibodies -- polymyxin; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.05.019
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: While traditional drug discovery continues to be an important platform for the search of new antibiotics, alternative approaches should also be pursued to complement these efforts. We herein designed a class of molecules that decorate bacterial cell surfaces with the goal of re-engaging components of the immune system toward Escherichia coli and Pseudomonas aeruginosa . More specifically, conjugates were assembled using polymyxin B (an antibiotic that inherently attaches to the surface of Gram-negative pathogens) and antigenic epitopes that recruit antibodies found in human serum. We established that the spacer length played a significant role in hapten display within the bacterial cell surface, a result that was confirmed both experimentally and via molecular dynamics simulations. Most importantly, we demonstrated the specific killing of bacteria by our agent in the presence of human serum. By enlisting the immune system, these agents have the potential to pave the way for a potent antimicrobial modality. Graphical Abstract: Highlights: Polymyxin was modified to include endogenous haptens Agents triggered the recruitment of antibodies to cell surfaces Targeting of Gram-negative pathogens was observed in culture and in live C. elegans Abstract : Feigman et al. describe a mode of re-engaging components of the immune system to target Gram-negative bacteria for destruction. By modifying polymyxin B to include antibody recruiting epitopes, bacterial cell surfaces were decorated with agents that triggered antibody binding and cell killing.